DESCRIPTION (taken from the application) The overall goal of this proposal is to define the causal determinants of the inverse relationship between insulin resistance and testosterone in men. Conducting studies in normal men, lean first degree relatives of type II diabetic patients, obese men with normal glucose tolerance, and men with type II diabetes will permit determination of whether the interaction between insulin resistance and testosterone is independent of body weight and glucose tolerance. Given the significant cardiovascular morbidity and mortality associated with obesity and type II diabetes, a clearer understanding of the interplay between testosterone and insulin resistance has important public health implications and may potentially facilitate the development of new therapeutic strategies for these extremely common metabolic disorders. Specific Aims 1-3 of this proposal will address the impact of insulin resistance on the reproductive axis in the male and will specifically: i) define the dose response relationship between increasing insulin resistance and testosterone secretion in men; ii) localize the defect induced in the hypothalamic-pituitary-gonadal (HPG) axis by insulin resistance using frequent blood sampling studies as well as GnRH and hCG testing after endogenous gonadotropin blockade with a GnRH antagonist; and iii) examine the impact on the HPG axis of reducing insulin resistance with a thiazolidinedione in men with type II diabetes. Specific Aims 4 and 5 will address the impact of testosterone on insulin resistance and will specifically: iv) define the dose-response relationship between increasing testosterone and insulin resistance by measuring insulin sensitivity with a glucose clamp after induction of hypogonadism with a GnRH agonist and again after both physiologic and pharmacologic testosterone replacement; and v) examine the impact of testosterone treatment on insulin resistance and glycemic control in type II diabetes. The selective and sequential manipulation of sex steroid and insulin levels as outlined in this proposal will permit precise definition of the relationship between testosterone and insulin resistance in men to be established and their causative determinants unequivocally defined.